1. Field of the Invention
The invention is a cosolvent parenteral pharmaceutical formulation of lazaroid compounds.
2. Description of the Related Art
International Publication No. WO87/01706 based on International Patent Application No. PCT/US86/01797 and U.S. Pat. No. 5,175,281 disclose 21-4-2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl!-1-piperazinyl!-16.alpha.-met hylpregna-1,4,9(11)-triene-3,20-dione (EXAMPLE 83), which is known as tirilazad, and the mesylate salt (EXAMPLE 109) which is known as tirilazad mesylate for use as neurological agents.
The Journal of Pharmacology and Experimental Therapeutics, 269, 145-50 (1994), International Journal of Clinical Pharmacology and Therapeutics, 32, 223-230 (1994) and Pharmaceutical Research, 11(2) 341 (1994) disclose 21-4-2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl!-1-piperazinyl!-16.alpha.-met hyl-5.alpha.-pregna-1,9(11)-diene-3,20-dione (5.alpha.-tirilazad).
U.S. patent application Ser. No. 08/278,633 discloses 21-4-2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl!-1-piperazinyl!-16.alpha.-met hyl-5.alpha.-pregna-1,9(11)-diene-3,20-dione (5.alpha.-tirilazad) and the 5.beta.-isomer (5.beta.-tirilazad) and pharmaceutically acceptable salts thereof.
U.S. patent application Ser. No. 08/361,818 discloses 6.alpha.-hydroxy-21-4-2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl!-1-piperazin yl!-16.alpha.-methylpregna-1,4,9(11)-triene-3,20-dione (6.alpha.-hydroxytirilazad) and 6.beta.-hydroxy-21-4-2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl!-1-piperaziny l!-16.alpha.-methylpregna-1,4,9(11)-triene-3,20-dione (6.beta.-hydroxytirilazad) and pharmaceutically acceptable salts thereof.
U.S. Pat. No. 4,968,675 discloses a parenteral formulation of tirilazad mesylate in citrate buffer. The present invention in addition uses a cosolvent which causes less irritation and pain when used as intended (diluted).
Cosolvents have become widely used as a means for solubilizing drugs for non-parenteral and parenteral (both IV and IM) administration. The effect is dependent primarily upon the polarity of the drug with respect to the solvent (water) and the cosolvent. The degree to which the solubility of a drug can be increased for a particular cosolvent is dependent upon the nonpolarity of the drug and the nonpolarity of the cosolvent. The most frequently used cosolvents are propylene glycol, ethanol, glycerine, and polyethylene glycol. The solubilization curves of a number of pharmaceutically important solutes in cosolvent systems is known, Techniques of Solubilization of Drugs, edited by S. H. Yalkowsky, Marcel Dekker, INC 1981, more particularly see Solubilization of Drugs by Cosolvents, p 91-134.
U.S. Pat. No. 4,794,117 and International Publication No. WO85/04106 disclose that solubilization of hydrophobic pharmaceuticals, e.g. steroids, may be accomplished by solution in polyethylene glycol and addition of aqueous solutions of controlled pH and buffering.
Buffers in parenteral formulations are known.
Journal of Pharmaceutical Science and Technology, 48, 86-91 (1994) discloses that for that particular drug lower acetate buffer concentration caused less irritation than higher acetate buffer concentration. It was further disclosed that citrate buffer concentration of 0.01M caused less irritation than acetate buffer concentration at 0.005M with the particular drug used.